Showing papers by "R. Rajasekaran published in 2014"
TL;DR: The findings provide knowledge to understand the structural and functional relationship of disease-causing mutations, R32Q and T53I on SAP as well as gain further insights into the molecular pathogenesis of the XLP syndrome.
Abstract: X-linked lymphoproliferative (XLP) syndrome is an extremely rare inherited immunodeficiency disease characterized by severe immune dysregulation caused by mutations in signaling lymphocyte activation molecule (SLAM) associated protein (SAP) gene. The XLP syndrome was manifested due to dysfunction of SAP as a result of amino acid substitution. Hence, to understand the molecular aspects of the XLP syndrome, we structurally characterized two observed mutations, R32Q and T53I on SAP through the systematic molecular dynamics (MD) approach. Our MD analysis showed that mutant structures elucidated an atomic level variation influenced by mutations that substantially altered the residual flexibility and more importantly the hot spot residues as well in unbound and bound systems. In addition, change in residual flexibility of mutant structures showed an unusual conformational behavior associated with their molecular recognition function compared to the wild-type SAP in both systems. Besides, both mutant structures established different secondary structural profiles during the course of the simulation period in both systems. Moreover, the docking analysis revealed that mutant R32Q and T53I structures displayed remarkably reduced levels of binding affinity to the unphosphorylated SLAM peptide with respect to their docking scores. Collectively, our findings provide knowledge to understand the structural and functional relationship of disease-causing mutations, R32Q and T53I on SAP as well as gain further insights into the molecular pathogenesis of the XLP syndrome.
13 citations
TL;DR: Computational evidences suggested that E17K, E17S, E319G, L357P, and P388T variants of AKT1 could destabilize the protein networks, thus causing functional deviations of protein to some extent and strongly indicate that screening for these variants may be useful for disease molecular diagnosis and also to design the potential AKT inhibitors.
Abstract: The AKT1 gene is of supreme importance in cell signaling and human cancer. In the present study, we aim to understand the phenotype variations that were believed to have the highest impact in AKT1 gene by different computational approaches. The analysis was initiated with SIFT tool followed by PolyPhen 2.0, I-Mutant 2.0, and SNPs&GO tools with the aid of 22 nonsynonymous (nsSNPs) retrieved from dbSNP. A total of five AKT1 variants such as E17K, E17S, E319G, L357P, and P388T are found to exert deleterious effects on the protein structure and function. Furthermore, the molecular docking study indicates the lesser binding affinity of inhibitor with the mutant structure than the native type. In addition, root mean square deviation and hydrogen bond details were also analyzed in the 10 ns molecular dynamics simulation study. These computational evidences suggested that E17K, E17S, E319G, L357P, and P388T variants of AKT1 could destabilize the protein networks, thus causing functional deviations of protein to some extent. Moreover, the findings strongly indicate that screening for AKT1, E17K, E17S, E319G, L357P, and P388T variants may be useful for disease molecular diagnosis and also to design the potential AKT inhibitors.
4 citations
01 Jan 2014
TL;DR: Pre diagnosis of possible deleterious variations of the FOX C2 gene would help predict the possible onset of a disease and further developing personalized drug to treat a particular disease.
Abstract: Forkhead Box C2 gene plays an important role in the development of mesenchymal tissues. A mutation caused in FOXC2 gene leads to lymphedema-distichiasis. These variations occur mainly due to nsSNPs. Computational analysis of the SNPs occurring in this gene was done using SIFT, PolyPhen 2.0, I MUTANT 3.0, PANTHER, PhD SNP and SNPs & Go. The analysis unveils that out of 38 variants of this gene, 5 (I98V, I98M, P140L, R121H and S125L) were found deleterious by all the 6 servers. T147I was found damaging except by SNP&GO. Further the interaction between the different variants and protein was done using the STRING 9.05. The current study investigated the possible deleterious variations of the FOX C2 gene. Pre diagnosis of these variants would help predict the possible onset of a disease and further developing personalized drug to treat a particular disease.
1 citations